Exercise capacity, iron deficiency and depressive symptoms in patients with asymptomatic chronic systolic heart failure

Background: Iron deficiency (ID) is a common comorbidity in symptomatic heart failure (HF). It is associated with lower exercise capacity, anemia and poor quality of life and has proven to be a successful therapeutic target. In asymptomatic heart failure (NYHA 1) with reduced ejection fraction (HFrEF) however, prevalence of ID and its impact on exercise capacity, anemia and depressive symptoms are unknown.Methods: We analyzed 364 asymptomatic HFrEF patients for ID, ID-associated impairment of exercise capacity, anemia, inflammation, ventricular overload and depressive symptoms. Exercise capacity was measured by 6-minute walk test (6 MWT), peak oxygen consumption per kg bodyweight (peak VO2) and breathing efficiency (VE-VCO2 slope). ID was defined as ferritin <100 µg/L or ferritin 100-299 µg/L with transferrin saturation (TSAT) <20% [European Society of Cardiology (ESC) guideline-recommended definition]. Iron status was also assessed by serum soluble transferrin receptor (sTfR). Inflammation was defined as serum C-reactive protein >5 mg/L. Depressive symptoms were diagnosed by Hospital Anxiety and Depression-Scale (HADS-D) score ≥11 and Patient Health Questionnaire 9 (PHQ-9) score≥10. Results: Prevalences were 36.5% (29.3% absolute, 7.2% functional) for ID, 11% for anemia, 15.3% for inflammation and 6.5% (HADS-D) and 9.8% (PHQ-9) for depressive symptoms. The latter were similar in patients with/without ID (6.7% vs. 6.4%, p=0.46). Patients with ID had lower breathing efficiency (26.8±6.4 vs. 25.2±6.1, p=0.015), lower 6 MW distance (557 m±99 vs. 577 m±84, p=0.030), higher NT-pro BNP (545 ng/l [201; 1226] vs. 428 ng/L [195; 783], p=0.047), more often anemia (15.9% vs. 8.2%, p=0.015) and inflammation for functional ID (8/25 vs. 13/101, p=0.015). Patients with a TSAT<20% had lower 6 MW distance than those with a TSAT 20-25% or >25% (565±90 vs. 581±74 vs. 589±86 ms, p=0.003). In univariate regression models, we found higher sTfR to be associated with anemia (r=0.122, p<0.015), inflammation (r=0.118, p<0.02), ventricular overload (r=0.202, p<0.001) and lower exercise capacity in form of 6 MW distance (r=-0.138, p=0.007), which is similar to ID by ESC definition. In multivariable regression, only NT-pro BNP and in trend ID by ESC definition independently predicted lower breathing efficiency (p<0.001 and p=0.055, r=0.295). NT-pro BNP>1400 ng/L yielded 90% specificity for ID in ROC analysis. Conclusions: ID is a common comorbidity already in asymptomatic HFrEF patients. In a multivariable model, NT-pro BNP and in trend ID independently predicted lower breathing efficiency. NT-pro BNP>1400 ng/L yielded 90% specificity for ID. An association of ID with worsening of breathing efficiency and transition to higher NYHA classes should be subject of further studies.